The present invention, in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to novel RNA Polymerase I inhibitors and to uses thereof in methods of treating medical conditions including, for example, autoimmune diseases multiple sclerosis and proliferative diseases such as cancer.
Autoimmune diseases are caused by an autoimmune response, i.e., an immune response directed to a substance in the body of the subject. The characteristics of the autoimmune diseases vary and depend on the site affected by the autoimmune response.
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS) affecting young adults (disease onset between 20 to 40 years of age) and is the third leading cause for disability after trauma and rheumatic diseases, with an estimated annual cost of 34,000 USD per patient (total life time cost of 2.2 million USD per patient).
The disease is characterized by destruction of myelin, associated with death of oligodendrocytes and axonal loss. The main pathologic finding in MS is the presence of infiltrating mononuclear cells, predominantly T lymphocytes and macrophages, which surpass the blood brain barrier and induce an active inflammation within the brain and spinal cord. The neurological symptoms that characterize MS include complete or partial vision loss, diplopia, sensory symptoms, motor weakness that can worsen to complete paralysis, bladder dysfunction and cognitive deficits, which eventually may lead to a significant disability. The associated multiple inflammatory foci lead to myelin destruction, plaques of demyelination, gliosis and axonal loss within the brain and spinal cord and are the reasons which contribute to the clinical manifestations of neurological disability.
The etiology of MS is not fully understood. The disease develops in genetically predisposed subjects exposed to yet undefined environmental factors and the pathogenesis involves autoimmune mechanisms associated with autoreactive T cells against myelin antigens. It is well established that not one dominant gene determines genetic susceptibility to develop MS, but rather many genes, each with different influence, are involved.
Clinically, in 85% of MS patients the illness is initiated with a relapsing-remitting course (RRMS), and in about 10-15% of MS patients have an a-priori primary progressive course (PPMS) without relapses. RRMS is characterized by inflammatory attacks associated with neurological deficits with periods of remissions between the relapses that vary in time. After a period of 10 years, about 50% of RRMS patients will progress to a secondary progressive MS (SPMS) course, characterized by permanent neurological dysfunction, with or without relapses and progressive disability.
Benign MS (BMS) is a clinical variant of RRMS in which the patients develop low neurological disability if at all after a disease duration of at least 10 years. Accordingly, this group of MS patients do not experience devastating accumulating disability over-time and when these patients are examined neurologically and scored by the Expanded Disability Status Scale (EDSS) they receive a score that is equal to or lower than 3.0. This low EDSS score signifies mild disability and when this low disability occurs more than 10 years after disease onset, the course of MS is defined as benign. Prediction of patients that will have BMS is currently impossible and the definition of these patients is retrospective. The molecular events accountable for the BMS variant of disease are not understood.
WO 2008/081435 discloses methods and kits for predicting the prognosis of a subject diagnosed with multiple sclerosis and methods of selecting a treatment regimen of a subject diagnosed with multiple sclerosis.
Achiron A, et al., 2007 [Clinical and Experimental Immunology, 149: 235-242] describe genes of the zinc-ion binding and cytokine activity regulation pathways which predict outcome in relapsing-remitting multiple sclerosis.
WO 2010/113096 discloses methods of predicting clinical course and treating multiple sclerosis.
Current approved drugs for the treatment of MS are either general anti-inflammatory agents or immunomodulators and consequently result only in moderate beneficial effects suppressing disease activity.
CX-5461 (see, Table 1 hereinunder) is a small molecule that was designed to selectively inhibit rRNA synthesis by inhibiting RNA Polymerase I (POL I or POL1), without affecting mRNA synthesis by RNA Polymerase II (POL II), and without inhibiting DNA replication or protein synthesis (Russell J, Zomerdijk J C. Trends Biochem Sci 30:87-96, 2005; Drygin D, et al. Annu Rev Pharmacol Toxicol 50:131-156, 2010).
The inhibition of POL1 results in nucleolar stress which causes the release of ribosomal proteins (RP) from the nucleolus and subsequent activation of p53, resulting in cell apoptosis [Kalita K, et al. J Neurochem 105:2286-2299, 2008]. In a previous study [Drygin D, et al. Cancer Res 71:1418-1430, 2011], the antiproliferative activity of CX-5461 was studied in cell lines and it was shown that CX-5461 inhibited POL-I activity in human cancer cell lines.
Recent studies indicate that disruption of the SL1/rDNA complex by CX-5461 results from the interference between SL1 and rDNA. SL1, a protein complex containing TATA binding protein-associated factors, is responsible for POL1 promoter specificity. SL1 performs important tasks in the transcription complex assembly, mediating specific interactions between the rDNA promoter region and the POL1 enzyme complex, thereby recruiting POL1, together with a collection of POL1-associated factors like RRN3 to rDNA (Cavanaugh A, et al. Gene Expr 14:131-147, 2008).
U.S. Patent Application Publication No. 2009/0093465 discloses a family of compounds, including CX-5461, as kinase modulators useful in the treatment of proliferative diseases such as cancer.
Recently, a role for inhibition of RNA polymerase I (POL1) pathway in the regulation of MS disease activity by suppression of inflammation and enhancement of apoptosis of autoreactive lymphocytes has been uncovered. The suggested mechanism by which POL1 pathway inhibition affects the disease process is demonstrated in Background Art FIGS. 1 and 2A-B.
The above findings have supported a basis for direct targeting of RNA Polymerase-I transcription pathway as a strategy for selective induction of apoptosis in MS in order to transform the active disease of RRMS to the preferable BMS subtype. Administration of a specific POL1 inhibitor (POL1-I) was demonstrated to prevent animal Experimental Autoimmune Encephalomyelitis (EAE) when administered at disease induction and to reduce the disease severity when administered at clinical disease onset [Achiron et al. 2013, J Neuroimmunol 263:91-97], thus confirming that a POL1 inhibitor acts specifically by inhibiting the polymerase I associated molecules.
WO 2012/123938 discloses uses of family of compounds, including CX-5461 and derivatives thereof, in the treatment of autoimmune diseases such as MS.
Additional background art includes Leuenroth S J and Crews C M (Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure. Cancer Res. 2008; 68:5257-5266); Liu Y, et al. (Triptolide, a component of Chinese herbal medicine, modulates the functional phenotype of dendritic cells. Transplantation. 2007; 84:1517-1526); Wang Y, et al. (Triptolide modulates T-cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. J Neurosci Res. 2008; 86:2441-2449; EP 0983256; PCT/US1998/008562; WO9852933A1; Alice H. Cavanaugh, et al., 2002 (Rrn3 Phosphorylation is a regulatory checkpoint for ribosome biogenesis J. Biol. Chem., 2002; 277: 27423-27432); PCT Pub. No. WO 03/081201.